Venetoclax and Acalabrutinib in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma

PRIMARY OBJECTIVES: I. To evaluate the efficacy of a combination of venetoclax and acalabrutinib, in patients with previously treated relapsed/refractory mantle cell lymphoma (MCL). SECONDARY OBJECTIVES: I. To evaluate the efficacy of this combination regimen in previously treated subjects with relapsed/refractory MCL with overall response rate (ORR), duration of response (DOR), event free survival (EFS), progression free survival (PFS), and overall survival (OS). II. To evaluate the safety and tolerability of venetoclax and acalabrutinib in previously treated subjects with relapsed/refractory MCL. CORRELATIVE/TRANSLATIONAL COMPONENT OBJECTIVES: I. Sequential peripheral blood (PB)/plasma/tissue fine needle aspirate will be stored. II. Clonal evolution with targeted sequencing (seq) and/or whole exome sequencing (WES) in sequential samples. III. Pattern of mutation changes with Bruton tyrosine kinase inhibitor (BTKi) or with venetoclax resistance. IV. Response predictors - mutations, cytokine-chemokines, clonal evolution (CE). V. Minimal residual disease (MRD) assay using circulating tumor deoxyribonucleic acid (ctDNA) analysis, flow cytometry at various time points from peripheral blood (PB)/ bone marrow (BM). VI. Sequential immunologic studies with cytokines/chemokines, T cell numbers, and immunoglobulins (Ig). VII. Tissue microenvironmental studies with simultaneous assessment of PB, BM and lymph nodes for gene expression profiling (GEP), single cell seq, ribonucleic acid (RNA) seq and clonal heterogeneity and the impact of acalabrutinib - venetoclax (A-V) treatment. OUTLINE: This is a dose escalation study of venetoclax. Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28. Starting cycle 2 day 1, patients also receive venetoclax PO daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up within 30 days, then every 4 months for 2 years, then every 6 months for the next 2 years, and then annually thereafter.